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Short report
Detection of APC germ line mosaicism in patients with de novo familial adenomatous polyposis: a plea for the protein truncation test
  1. Judith Necker1,
  2. Michal Kovac1,
  3. Michèle Attenhofer1,
  4. Bruno Reichlin2,
  5. Karl Heinimann1
  1. 1Research Group Human Genetics, Department of Biomedicine and University Children's Hospital, University of Basel, Switzerland
  2. 2Museggrain 2, CH-6004 Lucerne, Switzerland
  1. Correspondence to Karl Heinimann, Research Group Human Genetics, Department of Biomedicine, Mattenstrasse 28, Basel 4058, Switzerland; karl.heinimann{at}


Background Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposition caused by germ line mutations in the APC (adenomatous polyposis coli) gene. Current recommendations for APC mutation analysis advise full gene sequencing to identify point mutations and small insertions/deletions as well as the multiplex ligation dependent probe amplification (MLPA) technique to detect gene dosage alterations. Use of the protein truncation test (PTT) as a pre-screening tool has thus been largely replaced with direct end-to-end sequencing, mainly because of its limited sensitivity and failure to identify APC missense alterations.

Methods and results This report describes two unrelated patients with classical polyposis coli and unremarkable family history in whom neither full sequencing nor MLPA on leucocyte derived DNA could identify a pathogenic APC mutation. Applying the PTT, however, provided evidence of aberrant bands in both patients. Subsequent targeted mutation analysis of their tumour derived DNA allowed the identification of two novel, pathogenic APC alterations present in a mosaic state, at blood levels (1–15%) below the detection limits of conventional Sanger sequencing.

Conclusion The findings demonstrate the value of the PTT in identifying mosaic mutations in apparently APC mutation negative FAP patients with de novo classical polyposis and the need to keep the PTT within the diagnostic repertoire for APC mutation analysis.

  • Clinical genetics
  • genetic screening/counselling
  • molecular genetics
  • cancer: colon

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  • Funding The study was supported by grants from the Krebsliga beider Basel and Oncosuisse.

  • Competing interests None to declare.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Ethikkommission beider Basel (“Basler Studie über familiaere Tumorkrankheiten”, Nr. 258/05).

  • Provenance and peer review Not commissioned; externally peer reviewed.